Sepsis is a clinical syndrome that results from a harmful or damaging host response to infection or insult. Sepsis is characterized by a highly complex and integrated response that includes activation of various cell types that are inflammatory mediators. Cytokines play a central role in inflammation, and neutralization of the cytokines involved in the pathogenesis of inflammatory diseases is an established therapeutic modality. The goal of this study is to design new compounds and/or peptides to block tyrosine kinase 2 (TYK2) function. TYK2 is a receptor-associated kinase used by a restricted number of cytokines, including IFN-b, IL- 23, and IL-27 that have been shown to play a role in sepsis. Type I and type II cytokine receptors lack receptor-intrinsic tyrosine kinase activity and instead transmit signals through receptor-associated Janus kinases (JAKs). A member of the JAK family, TYK2 may be a better target than other JAks, because of potential less serious side effects. We hypothesize that targeting TYK2 could be effective in treating sepsis. Our goal in the proposed research is to develop TYK2-specific and -selective inhibitors to (1) enhance our understanding of the role of TYK2 in sepsis, and (2) further the long-term development of new therapeutics for sepsis. In Specific Aim 1, the crystal structure will be used to identify specificty opportunities for TYK2 to design inhibitors and to select potential inhibitors from our library of chemical entities. As a parallel approach, we will design and synthesize peptides to inhibit TYK2. In Specific Aim 2, enzymatic and cellular assays will be performed to validate the selected or synthesized compounds and peptides, and selected compounds/peptides will be validated in vivo using mouse models of sepsis. Ultimately, this research will lead to a better understanding of the role of TYK2 in inflammatory diseases such as sepsis and provide novel and validated compounds that can be pursued for drug discovery.